Biomedical subjects
Publications and source records attributed to L B Rosen.
Forty consecutive 90-year-old persons with an acute myocardial infarction were studied to describe the noncardiac complications of their care. Common negative consequences of hospitalization of these patients included delirium, pressure ulcers, and poor ambulatory status at discharge.
To understand the mechanisms by which electrical activity may generate long-term responses in the nervous system, we examined how activation of voltage-sensitive calcium channels (VSCCs) can stimulate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Calcium influx through L-type VSCCs leads to tyrosine phosphorylation of the adaptor protein Shc and its association with the adaptor protein Grb2, which is bound to the guanine nucleotide exchange factor Sos1. In response to calcium influx, Shc, Grb2, and Sos1 inducibly associate with a 180-kDa tyrosine-phosphorylated protein, which was determined to be the epidermal growth factor receptor (EGFR). Calcium influx induces tyrosine phosphorylation of the EGFR to levels that can activate the MAPK signaling pathway. Thus, ion channel activation stimulates growth factor receptor signal transduction.
Tyrosine kinase receptors stimulate the Ras signalling pathway by enhancing the activity of the SOS nucleotide-exchange factor. This occurs, at least in part, by the recruitment of an SOS-GRB2 complex to Ras in the plasma membrane. Here we describe a different signalling pathway to Ras that involves activation of the Ras-GRF exchange factor in response to Ca2+ influx. In particular, we show that the ability of Ras-GRF to activate Ras in vivo is markedly enhanced by raised Ca2+ concentrations. Activation is mediated by calmodulin binding to an IQ motif in Ras-GRF, because substitutions in conserved amino acids in this motif prevent both calmodulin binding to Ras-GRF and Ras-GRF activation in vivo. So far, full-length Ras-GRF has been detected only in brain neurons. Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals.
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A pathway by which calcium influx through voltage-sensitive calcium channels leads to mitogen-activated protein kinase (MAPK) activation has been characterized. In PC12 cells, membrane depolarization leading to calcium influx through L-type calcium channels activates the dual specificity MAPK kinase MEK1, which phosphorylates and activates MAPK. Calcium influx leads within 30 s to activation of the small guanine nucleotide-binding protein Ras. Moreover, activation of MAPK in response to calcium influx is inhibited by the dominant negative mutant RasAsn17, indicating that Ras activity is required for calcium signaling to MAPK. Ras is also activated by release of calcium from intracellular stores and by membrane depolarization of primary cortical neurons. The pleiotropic regulatory potential of both Ras and the MAPK pathway suggests that they may be central mediators of calcium signaling in the nervous system.
BACKGROUND: Seabather's eruption (SE) is a highly pruritic eruption under swimwear that occurs after bathing in the ocean. Its cause has been unknown. Few data have been collected since the classic description by Sams in 1949. OBJECTIVE: Our purpose was to describe the clinical and histopathologic findings in SE and to confirm the cause. METHODS: Patients with a pruritic eruption that developed after swimming were seen within 1 week of onset. Skin biopsy specimens and sera were obtained in selected cases. Water samples taken from areas of active SE outbreaks were examined for a causative organism. Sera were tested by enzyme-linked immunosorbent assay for reactivity to this organism. RESULTS: In southeast Florida, during a 4-month period, 70 patients with SE were seen. Inflammatory papules and pruritus were noted within hours of exposure. Eruptions were maximal in areas covered by a bathing suit. Children were more likely than adults to have systemic symptoms. The average duration of the eruption and pruritus was 12.5 days, with recurrences in 4.3% of patients. Histopathologic examination revealed a superficial and deep perivascular and interstitial infiltrate consisting of lymphocytes, neutrophils, and eosinophils. Water samples contained many cnidarian larvae, later grown to maturity and identified as Linuche unguiculata (thimble jellyfish). Enzyme-linked immunosorbent assay demonstrated in patients' sera high IgG levels specific for L. unguiculata. CONCLUSION: SE is a severely pruritic marine dermatosis that resolves spontaneously within 2 weeks. Therapy is symptomatic but often ineffective. Sera from affected persons showed specific reactivity to L. unguiculata.
The human glycoprotein alpha-subunit is the common subunit of the heterodimeric hormones CG (hCG), TSH, LH, and FSH. Human glycoprotein alpha-subunit is produced eutopically in placenta, pituitary, and choriocarcinoma and ectopically in a large variety of human tumors. We report ectopic glycoprotein alpha-subunit messenger RNA (mRNA) and peptide production in the human hepatoma cell line, NPLC. Neither hCG beta mRNA nor intact hCG peptide was detected. Antimetabolite regulation of glycoprotein alpha-subunit expression in NPLC cells resembled that found in choriocarcinoma cells in that it was stimulated by hydroxyurea. In addition, glycoprotein alpha-subunit mRNA expression and transcription in NPLC were stimulated by activators of the protein kinase A and C second messenger pathways, as well as by glucocorticoid. Glucocorticoid augmented glycoprotein alpha-subunit gene transcription by phorbol ester and forskolin, in contrast to its simultaneous inhibitory effect on phorbol ester activation of the CRH gene, which is also ectopically expressed in these cells. Glucocorticoid thus modulates the activation of these genes by phorbol ester in opposite directions, despite their identical cellular context. The NPLC cell line provides a new model for the study of human glycoprotein alpha-subunit gene regulation and free glycoprotein alpha-subunit secretion. In addition, it should be useful for investigating the role that specific cis-acting DNA sequences play in glucocorticoid modulation of gene induction by second messenger pathways.
We have examined the regulation of the hypothalamic secretagogue CRH by glucocorticoid and the protein kinase-A and -C second messenger pathways in cultured cells. We show that the human primary liver carcinoma NPLC expresses the endogenous CRH gene. Dexamethasone reduced CRH mRNA levels by more than 90%, with half-maximal suppression at 5 nM. Phorbol ester treatment to activate the protein kinase-C pathway increased CRH mRNA levels up to 30-fold, whereas forskolin treatment to activate the protein kinase-A pathway had no effect. In coincubation experiments, dexamethasone completely suppressed phorbol ester-induced CRH mRNA levels in NPLC cells, maintaining them at the levels seen in untreated cells. We contrasted this regulation with the effects of glucocorticoid on CRH mRNA induction by forskolin in R1, a mouse anterior pituitary cell line (AtT-20) stably transfected with the human CRH gene. Dexamethasone suppressed forskolin-induced CRH mRNA levels by 70% in R1 cells, but only to levels that were still 10-fold greater than those in untreated cells. These results suggest that CRH induction in vivo by ligands that act via protein kinase-A may be less effectively suppressed by glucocorticoid feedback than CRH induction by ligands that act via protein kinase-C. This differential effect of glucocorticoid on CRH mRNA regulation could help explain the abnormal CRH production observed in clinical disorders such as anorexia nervosa and major depression.
We have studied the effect of protein kinase-C activation on the regulation of CRH gene expression in the human hepatoma cell line NPLC/PRF/5 (NPLC), the only cell line known to express the endogenous CRH gene. Incubation of NPLC cells with 100 nM 12-O-tetradecanoyl phorbol 13-acetate (TPA), a phorbol ester that activates protein kinase-C, resulted in a rapid (1-h) and prolonged (72-h) increase in CRH mRNA levels, with the maximum increase of 16-fold observed at 24 h. In addition, TPA treatment increased the size of CRH mRNA by approximately 100 nucleotides. This size increase, which was blocked by protein synthesis inhibitors, occurred within 1 h of TPA addition and lasted at least 8 h, with a return toward the baseline size by 24 h. Structural analysis of CRH mRNA revealed two poly(A) addition sites and, as found in human placenta, multiple transcription start sites. The increase in CRH mRNA size was not due to changes in the sites of either transcription initiation or poly(A) addition, but, rather, to a 3-fold increase in the length of the poly(A) tail itself. The ability of TPA to increase CRH mRNA levels in NPLC cells suggests that the protein kinase-C second messenger pathway may be involved in the physiological regulation of CRH gene expression. Increases in CRH mRNA poly(A) tail length potentially may influence CRH mRNA stability or translatability and, thus, may represent a general mechanism by which the protein kinase-C pathway can influence gene expression.
To evaluate coronary flow reserve during cardiac catheterization, intracoronary adenosine and papaverine have been used in the clinical setting. Although papaverine maximizes coronary blood flow, it induces several toxic side effects that reduce its desirability as a coronary dilator. This investigation was designed to compare the subselective intracoronary administration of papaverine with that of adenosine in an animal model. In dogs (n = 34), we studied the effects of each agent on hemodynamics, regional myocardial blood flow, contractility (sonomicrometric and echocardiographic), metabolism (coronary arterial and venous lactate and tissue high-energy phosphates), and electrocardiographic (ST and QT intervals) parameters. Barbiturate and morphine anesthesia/analgesia was induced, and a left thoracotomy was performed. An arterial shunt was created from the left carotid artery to the left anterior descending coronary artery. Two separate groups were studied: group 1 (n = 16) for regional myocardial blood flow and mechanical function and group 2 (n = 18) for biochemical measurements. Adenosine (67 +/- 2 micrograms/min) or papaverine (6 +/- 1 mg/min) was infused into the coronary shunt at a rate of 0.5 + 0.1 ml/min for a maximum duration of 3.5 minutes. Regional myocardial blood flows were determined at control (predrug) and maximal coronary flow using radiolabeled microspheres. All hemodynamic, wall motion, biochemical, and electrocardiographic parameters were also measured at these times. Both drugs produced comparable increases in total and regional coronary blood flows (adenosine, 1.21 +/- 0.15 to 4.83 +/- 0.36 ml/min/g; papaverine, 1.21 +/- 0.05 to 4.89 +/- 0.28 ml/min/g) upon infusion into the left anterior descending coronary artery. Papaverine produced significant (p less than 0.05) changes in subendocardial ST segment electrocardiogram (-2.5 mm), QT prolongation (8 +/- 2%), myocardial creatine phosphate (47% decrease), and coronary sinus serum lactate (277% increase) compared with control. In addition, intracoronary papaverine induced an abnormal contractile pattern. No significant changes in any of these parameters (i.e., ST segment, QT prolongation, myocardial creatine phosphate level, or lactate level) were observed with intracoronary adenosine infusions. We conclude that intracoronary adenosine is comparable to papaverine for maximizing coronary blood flow without the deleterious properties observed with intracoronary papaverine.
A review and proposed new classification of benign acquired neoplasms which differentiate towards hair follicle structures is presented. Seventeen neoplasms are discussed with an in-depth review of the literature.
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Malignant endovascular papillary angioendothelioma is a rare vascular tumor of childhood that was first defined by Dabska in 1969. Microscopically, this tumor is composed of anastomosing vascular channels, some of which contain papillary projections or tuft-like structures sometimes resembling renal glomeruli. Although cases have been reported with metastases to regional lymph nodes, the long term prognosis for patients with these tumors is generally good. We have studied this tumor by light and electron microscopy as well as immunohistochemical techniques in a 10-year-old boy. A review of the literature on this rare entity is presented.
A 15-year-old white boy with a giant cell fibroblastoma of the skin of the abdomen is described. Giant cell fibroblastoma is a rare soft tissue neoplasm that most commonly occurs in children as a small, painless mass in the dermis and subcutaneous tissue. Although local recurrences have been reported, no metastases have occurred. Giant cell fibroblastoma must be differentiated from other spindle cell neoplasms.
We studied a polypoid cutaneous neoplasm excised from the left arm of a 23-year-old man by light microscopy, immunohistochemistry, and electron microscopy. Histologically, the tumor was composed of a proliferation of round to oval epithelioid cells that were arranged in fascicles and showed a prominent perineural distribution. Immunohistochemistry revealed the presence of S-100 protein and vimentin within tumor cells. Electron microscopy demonstrated reduplication of basal lamina and abundant long-spacing collagen in intercellular spaces. The findings are consistent with a primary malignant epithelioid schwannoma of the skin. We discuss the relationship of this lesion with other neoplasms in the spectrum of tumors showing schwannian and melanocytic lines of differentiation.
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Thirty-six cases of fibrous papules of the face and nose were studied by light microscopy and by immunohistochemistry. Positive staining with antibodies to vimentin and negative staining with antibodies to S-100 protein, alpha 1-antichymotrypsin, and factor VIII-RAG of the spindle, stellate, and multinucleated cells observed in the dermis support a fibroblastic line of differentiation. Fibrous papules of the nose and face are a distinctive clinicopathologic entity that most probably represents an inflammatory rather than a neoplastic process, sharing some histologic features of angiofibromas (angiofibrosis) and perifollicular fibromas (perifollicular fibrosis).
A case is presented of a multifocal malignant neoplasm involving the skin of the upper back in a 10-year-old boy following radiation therapy to the head and neck for a cerebellar medulloblastoma. Histologically, the neoplastic cells were remarkable for the presence of abundant periodic acid-Schiff (PAS)-positive diastase-resistant intracytoplasmic eosinophilic granules. Immunoperoxidase procedures revealed strong positive staining of the tumor cells with desmin, vimentin, and smooth muscle myosin antibodies, and negative staining for myoglobin, S-100 protein and keratin, thus supporting a smooth muscle line of differentiation for this neoplasm. Electronmicroscopy demonstrated numerous intracytoplasmic autophagic vacuoles that corresponded to the granules observed under the light microscope. Leiomyosarcoma should be entertained in the differential diagnosis of poorly differentiated cutaneous neoplasms histologically characterized by a proliferation of cells containing abundant granular eosinophilic cytoplasm.